Air Toxics Hot Spots Program

Risk Assessment Guidelines

Part III

Technical Support Document

for the Determination of

Noncancer Chronic

Reference Exposure Levels

Air Toxicology and Epidemiology Section

Office of Environmental Health Hazard Assessment

California Environmental Protection Agency

1515 Clay Street, 16th Floor

Oakland, California 94612

February 2000
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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DETERMINATION OF

NONCANCER CHRONIC

REFERENCE EXPOSURE LEVELS

February 2000

California Environmental Protection Agency

Office of Environmental Health Hazard Assessment

Air Toxicology and Epidemiology Section
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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Prepared by:

George V. Alexeeff, Ph.D.

John D. Budroe, Ph.D.

James F. Collins, Ph.D.

Daryn E. Dodge, Ph.D.

Jefferson R. Fowles, Ph.D.

John B. Faust, Ph.D.

Richard F. Lam, Ph.D.

David C. Lewis, Ph.D.

Melanie A. Marty, Ph.D.

Frank J. Mycroft, Ph.D.

Hugh Olsen, Ph.D.

Judy S. Polakoff, M.S.

Jean Rabovsky, Ph.D.

Andrew G. Salmon, M.A., D.Phil.

Office of Environmental Health Hazard Assessment

OEHHA also acknowledges the following contributors:

Sharan Campleman, Ph.D.

Peggy Lopipero, M.P.H.

Lee Moore, Ph.D.

Rene Paige, B.S.

Moira Sullivan, M.S.

Eileen Yates, B.S.

The authors would like to acknowledge the administrative and clerical support of

Myeast McCauley, Michelle Johnson, Laurie Bliss, Jacqueline Grayson, and Ursula Jones.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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Table of Contents

1. Introduction ................................................................................................................................. 5

1.1 Objective............................................................................................................................... 5

1.2 Implementation of Risk Assessment Committee (RAAC) Recommendations..................... 6

1.3 Priority for Evaluation of Chemicals.................................................................................... 8

1.4 Criteria for Development of Chronic Reference Exposure .................................................. 8

1.5 Population of Concern .......................................................................................................... 9

1.6 Exposure Concentration Averaging Period .......................................................................... 10

1.7 Effects of Multiple Chemical Exposures.............................................................................. 10

1.8 Preexisting Exposure Guidelines.......................................................................................... 11

1.8.1 U.S. EPA Reference Concentrations....................................................................... 11

1.8.2 U.S. EPA Reference Dose ....................................................................................... 11

1.8.3 Occupational Threshold Limit Values..................................................................... 11

1.8.4 California Ambient Air Quality Standards.............................................................. 12

2. Hazard Identification................................................................................................................... 12

2.1 Selection of Key Studies....................................................................................................... 12

2.1.1 Human Data ............................................................................................................. 12

2.1.1.1 Epidemiological Data........................................................................................ 12

2.1.1.2 Controlled Human Exposure Studies................................................................ 13

2.1.1.3 Case Reports...................................................................................................... 13

2.1.2 Animal Data............................................................................................................. 14

2.2 Weight of Evidence .............................................................................................................. 14

2.2.1 Strength of Associated Adverse Health Effect........................................................ 14

2.2.2 Consistency of Associated Adverse Health Effect.................................................. 15

2.2.3 Specificity of Associated Adverse Health Effect .................................................... 15

2.2.4 Temporal Association.............................................................................................. 15

2.2.5 Coherence of Adverse Health Effect....................................................................... 15

3. Dose Response Assessment ........................................................................................................ 15

3.1 Estimation of Threshold or Low Response Concentrations................................................. 15

3.1.1 Use of No-Observed-Adverse-Effect-Levels (NOAEL).......................................... 16

3.1.2 Use of Lowest-Observed-Adverse-Effect-Levels (LOAEL)................................... 16

3.1.3 Estimation of a Benchmark Concentration (BMC) ................................................. 18

3.2 Overview of Extrapolation from Study Data to Human Population..................................... 19

3.3 Effects of Exposure Continuity and Duration ...................................................................... 20

3.3.1 Differences between Continuous and Discontinuous Exposures............................ 20

3.3.2 Differences between Lifetime and Less-than-Lifetime Exposures ......................... 21

3.4 Differences between Human and Animal Susceptibility to Toxic Effects of Chemicals..... 22

3.4.1 Determination of a Human Equivalent Concentration ............................................ 22

3.4.1.1 Gases with Respiratory Effects......................................................................... 23

3.4.1.2 Gases with Systemic Effects............................................................................. 24

3.4.1.3 Particulates with Respiratory Effects................................................................ 24

3.4.2 Accounting for Potentially Greater Human Susceptibility...................................... 25

3.5 Increased Susceptibility of Sensitive Individuals................................................................. 26

3.6 Estimation of Inhalation Effects from Oral Exposure Data.................................................. 28

3.7 Summary of Extrapolation and Uncertainty Factors Used to Derive Chronic RELs........... 28

3.8 Documentation of Chronic Reference Exposure Levels ...................................................... 29

3.9 Chronic Reference Exposure Level Summary...................................................................... 29

4. References................................................................................................................................... 36
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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1. Introduction

Hazardous substances are routinely released into the environment due to predictable

continuous or intermittent emissions from facilities. As a result, people living or working in

communities surrounding such releases may be exposed to airborne toxicants. Local air pollution

control officers and industrial facility operators have a need for clear guidance about assessing

the chronic health effects of hazardous substances.

The National Academy of Sciences (NAS), through the National Research Council (NRC),

recommended that the U.S. EPA more clearly define, and in some cases change, the methods and

assumptions used to estimate the health risks of exposure to hazardous air pollutants (NRC,

1994). In particular, NAS has endorsed the development of biologically based quantitative

methods for assessing the health effects of chemical exposure. This includes incorporating

information on mechanisms of action and variability among populations and between individuals

that might affect susceptibility to harm, such as age, lifestyle, genetic background, sex, and

ethnicity. NAS acknowledged the continued need for default assumptions to address

uncertainties in assessing risks among a population. NAS has recommended that U.S. EPA (1)

identify each use of a default assumption in risk assessment; (2) clearly state the scientific and

policy basis for each default assumption; and (3) articulate criteria for allowing departure from

default assumptions. NAS also recommended that U.S. EPA screen the hazardous air pollutants

identified in the 1990 Clean Air Act Amendments to establish priorities for setting standards, to

identify data gaps, and to develop incentives to expedite the generation of data by other

governmental agencies.

The Office of Environmental Health Hazard Assessment (OEHHA) of the California

Environmental Protection Agency (Cal/EPA) has followed the NAS recommendations in this

document by establishing uniform, science-based guidelines to be used in the estimation of

chronic exposure levels to protect the general public from long-term exposure to hazardous

substances released into the environment.

1.1 Objective

The objective of this document is to present a method for deriving inhalation exposure levels

to protect the public from a lifetime of exposure to hazardous airborne substances. These healthbased chronic exposure levels are primarily for risk characterization of routine industrial

emissions. The guidelines for developing chronic inhalation exposure levels incorporate many

recommendations of the U.S. EPA (1994) and NAS (NRC, 1994).

As defined under the Air Toxics “Hot Spots” Information and Assessment Act of 1987

(California Health and Safety Code Section 44300 et seq.), a risk assessment includes a

comprehensive analysis of the dispersion of hazardous substances in the environment, the

potential for human exposure, and a quantitative assessment of both individual and populationwide health risks associated with those levels of exposure. This document establishes a
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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standardized procedure for generating the health based values (chronic reference exposure levels)

used for assessing chronic noncancer risks within the risk assessment process.

In preparing this document, OEHHA is responding to legislation enacted in California in

1992. Senate Bill (SB) 1731 (Statutes of 1992, Chapter 1162) requires OEHHA to develop risk

assessment guidelines for implementing the Air Toxics “Hot Spots” Act. Assembly Bill (AB)

2728 (Statutes of 1992, Chapter 1161, California Health and Safety Code Section 39660) added a

mandate to the Toxic Air Contaminant Program that all Federal Hazardous Air Pollutants be

identified as Toxic Air Contaminants. The Health and Safety Code also requires OEHHA to use

a margin of safety when estimating levels of exposure that may cause adverse health effects. This

margin of safety must account for diversity within human populations and for uncertainty related

to the applicability and completeness of the available data. To help meet these requirements,

OEHHA developed methods to estimate chronic exposure levels and derived such levels for

specific chemicals. The chronic exposure levels are designed for use in the Air Toxics “Hot

Spots” Program and the Toxic Air Contaminant Program but may have a variety of applications

to related programs.

OEHHA and the Air Resources Board (ARB) have set up a procedure to facilitate the

extensive public comment and peer review necessary for implementation of AB 2728 and SB

1731. This process includes workshops with the public and review by the Scientific Review

Panel on Toxic Air Contaminants administered by the ARB.

The substances listed by the ARB to be quantified under the Air Toxics “Hot Spots”

program were evaluated and considered for inclusion in this document. The substances on the Air

Toxics “Hot Spots” Program List include those (1) determined to be carcinogenic by the

International Agency for Research on Cancer (IARC), (2) listed by the U.S. EPA, including

hazardous air pollutants, (3) determined to be hazardous by the U.S. National Toxicology

Program (NTP), (4) determined by the ARB to be Toxic Air Contaminants, (5) determined to be

hazardous by the State of California Hazard Evaluation System and Information Service, or (6)

determined to be carcinogens or reproductive toxicants by the State of California under

Proposition 65. The complete list of substances that must be quantified is contained in Appendix

C of this document.

Other programs or agencies may also require review or development of chronic exposure

levels for other mandated or regulatory purposes. The methods described in this Technical

Support Document may be used in deriving these levels.

1.2 Implementation of Risk Assessment Advisory Committee (RAAC) Recommendations

The Cal/EPA RAAC is a panel of scientists convened under Chapter 418, Statutes of 1993,

Health and Safety Code, Section 57004, to review the health risk assessment practices within

Cal/EPA. The RAAC has issued a report on its findings (RAAC, 1996). In the completion of

this document, the RAAC recommendations were carefully considered.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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In general, the committee recommendations were well addressed (Table 1). Complete

implementation of all committee recommendations will require additional efforts beyond the

scope of the current project. In particular, developing alternative approaches to some areas of

uncertainty now addressed with default assumptions will require extensive data collection and

analyses.

Table 1. Implementation of RAAC Recommendations

RAAC

Recommendation

Implementation

Formalized peer

review program

This document has been reviewed by an advisory committee of nongovernmental scientists (the state’s Scientific Review Panel on Toxic

Air Contaminants).

Input from risk

managers and from

external

stakeholders

This document has been reviewed by risk assessors and managers of

the Cal/EPA Boards and Departments and by representatives of the

Air Quality Management and Air Pollution Control Districts. A

public comment period was held in October 1997 and June 1999.

The document has been distributed for comment to others, including

external stakeholders.

Balance level of

effort with

importance

The selection of chemicals for intensive review in this document was

based in part on the importance of the chemical within California.

Emphasis was placed on developing health levels for those

substances with high emissions or of concern to risk managers. The

project reviewed all available risk assessment information from U.S.

EPA and other authoritative bodies.

Coordinate effort

with U.S. EPA

The project made use of all available risk assessment information

from U.S. EPA. All U.S. EPA Reference Concentrations (RfCs)

which were available in May 1996 were evaluated on a case-by-case

basis. Methods followed in the development of new proposed RELs

were similar to those used by U.S. EPA.

Incorporate

consideration of

effect severity

Concerns that severely adverse and high incidence effects should be

addressed differently from mild and/or rarely encountered, lower

incidence effects were addressed by incorporation of intermediate (3-

fold) LOAEL uncertainty factors for the latter effects. Additional

research will be needed to implement more sophisticated approaches

to this problem.
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1.3 Priority for Evaluation of Chemicals

The 95 chemicals for which chronic noncancer reference exposure levels (RELs) appeared in

the California Air Pollution Control Officers Association (CAPCOA) Air Toxics “Hot Spots”

Program (Revised 1992) Risk Assessment Guidelines (CAPCOA, 1993) were considered for

evaluation. Additional chemicals were selected from the ARB list of Hot Spots substances for

which emissions need to be quantified. These substances were selected primarily based on (1)

the magnitude of current known emissions in California and (2) the availability of a strong

scientific database on which to estimate a chronic REL. The combined list of the 118 substances

that have been evaluated with the methods delineated in this Technical Support Document is

provided in Appendix B. Chronic RELs for an additional three substances, acetaldehyde, diesel

exhaust particulate, and perchloroethylene, have already been reviewed by the Scientific Review

Panel and adopted by the ARB.

1.4 Criteria for Development of Chronic Reference Exposure Levels

Chronic reference exposure levels are concentrations or doses at or below which adverse

health effects are not likely to occur. A central assumption is that a population threshold exists

below which adverse effects will not occur in a population; however, such a threshold is not

observable and can only be estimated. Areas of uncertainty in estimating effects among a diverse

human population exposed continuously over a lifetime are addressed using extrapolation and

uncertainty factors.

Protection against carcinogenicity and against adverse health effects of short-term exposures

are not considered in these guidelines. For this reason, chemicals should be evaluated separately

for their carcinogenic potential and additional acute health effects that may occur. Methods for

these evaluations are provided in the OEHHA documents entitled Air Toxics Hot Spots Program

Risk Assessment Guidelines. Part II. Technical Support Document for Describing Available

Cancer Potency Factors (1999) and Part I. Technical Support Document for the Determination of

Acute Reference Exposure Levels for Airborne Toxicants (1999).

The concentration, at or below which no adverse health effects are anticipated in the general

human population, is termed the reference exposure level (REL). RELs are based on the most

sensitive relevant adverse health effect reported in the medical and toxicological literature. RELs

are designed to protect the most sensitive individuals in the population by the inclusion of

margins of safety.

RELs are used by the Air Toxics “Hot Spots” Program as indicators of potential adverse

health effects. A “hazard index” approach is used to estimate potential health effects resulting

from hazardous substances by comparing measured or modeled exposure levels with RELs. This

approach assumes that the combination of multiple sub-threshold exposures could result in an

adverse health effect. (Please refer to the document titled CAPCOA Air Toxics Hot Spots

Program Revised 1992 Risk Assessment Guidelines (CAPCOA, 1993) for a detailed explanation

of this method. This document can be obtained from CAPCOA by calling (530) 676-4323 or

through their website at http://www.capcoa.org.)
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The health effects data for some chemicals are inadequate for the estimation of a REL. The

amount of data and the quality of the information will ultimately determine whether a chronic

REL is derived for a specific chemical. However, inclusions of margins of safety or uncertainty

factors can be used to address the common data gaps encountered in risk assessment. In many

cases, chronic RELs could not be developed. In these instances it was judged that the data were

not relevant to inhalation exposure, that too much uncertainty existed in the calculation, or that

development of a number based on the limited data could ultimately mislead or harm the public.

As more data become available over time, some chronic RELs may be added or reevaluated.

Exposure above a particular chronic REL may or may not lead to the development of

adverse health effects. Conversely, there may be individuals exhibiting idiosyncratic responses

(unpredictable health effects) at concentrations below the chronic RELs. Health effects

associated with individual chemicals are presented in Appendix A.

1.5 Population of Concern

Chronic RELs are designed to protect the individuals who live or work in the vicinity of

emissions of these substances. The general population consists of individuals with a wide range

of susceptibility (Figure 1). The susceptibility may be transitory or chronic. The general

population includes some people who are likely to be especially susceptible to developing

adverse effects (e.g., the very young, the elderly, pregnant women and those with acute or chronic

illnesses). Chronic RELs are intended to protect individuals with low susceptibility for chemical

injury as well as identifiable sensitive subpopulations (high-risk individuals) from adverse health

effects. Less susceptible individuals are healthy adults without any genetic or biological

predisposition that may increase the sensitivity to the chemical of concern. Highly susceptible or

sensitive individuals may include those with increased exposure (e.g., children, adults engaged in

physical activity), those undergoing greater physiological change (e.g., children, pregnant women

and their fetuses), individuals with impaired physiological conditions (e.g., elderly persons,

persons with existing diseases such as lung, heart or liver disease), and individuals with lower

levels of protective biological mechanisms due to genetic variability within the population (U.S.

EPA, 1990). However, the chronic RELs may not necessarily protect hypersensitive individuals

(those exhibiting idiosyncratic responses that cannot be predicted from studying the health effects

of the substance).

Because the true range of variability is unknown, there may be a proportion of the population

for whom the chronic RELs will not be fully protective. It is OEHHA’s intent that the levels will

protect nearly all individuals, including those identifiable at the high end of susceptibility.
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Figure 1. Distribution of human susceptibility to adverse effects of chemical exposure

1.6 Exposure Concentration Averaging Period

The exposure period of concern in the development of chronic RELs is a full lifetime, which

encompasses periods of potentially increased susceptibility to adverse health effects from

chemical exposure, particularly during childhood and the later years of life. The chronic REL is

intended to be protective for individuals exposed continuously over their lifetime. Scientific data

available to assess these effects generally consist of discontinuous exposures over a shorter

interval. In such cases default or chemical-specific assumptions are required to estimate

concentrations causing comparable effects if exposures were to be continued over the entire

lifetime. From a practical standpoint, chronic exposure for humans is considered to be greater

than 12% of a lifetime of 70 years. Thus, human exposures of greater than 8 years are considered

chronic exposures and are not adjusted either in their calculation or application.

1.7 Effects of Multiple Chemical Exposures

Concomitant exposures to more than one chemical may cause effects that are equal to, less

than, or greater than predicted from effects observed with exposures to the individual chemicals

(Ikeda, 1988; Jonker et al., 1990). Of the thousands of potential combinations of chemicals in

common use, only a small fraction have been tested for the potential that combined exposures

Relatively 

resistant 

Average

susceptibility 

Very 

susceptible

0%

50%

100%

Increasing concentration ------------->

Cumulative 

percent 

of persons 

responding
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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could have synergistic or antagonistic properties. The effects of multiple chemical exposures on

human health remain an area for future study.

1.8 Pre-Existing Exposure Guidelines

Chronic exposure levels have been derived using several different approaches. Furthermore,

inhalation exposure values estimated using a consistent basis to protect the general public,

notably the U.S. EPA RfCs, are available for only a few dozen chemicals. Other values designed

for the protection of the general public, in particular the U.S. EPA reference doses (RfDs), are

available for many more chemicals but are intended primarily to deal with non-inhalation

exposures to chemicals and are usually based on toxicity data obtained following ingestion or

dermal exposure. It is very likely that the ingestion and dermal routes would underestimate the

health effects of inhalation exposure, unless the health effect is an identifiable systemic effect. If

the effect is systemic, then appropriate adjustments for absorption can be made. Occupational

exposure guidelines, which are available for hundreds of substances, have been used in many

states to derive inhalation exposure guidelines for the general public. These values, however,

have an inconsistent basis and in many cases have not incorporated recently available data.

1.8.1 U.S. EPA Reference Concentrations

The U.S. EPA presented an inhalation reference concentration (RfC) method (Jarabek et al.,

1989; U.S. EPA, 1994). The RfC is comparable to earlier Acceptable Daily Intake (ADI) and

RfD methods but addresses inhalation specific issues such as respiratory dynamics and inhalation

delivered doses.

1.8.2 U.S. EPA Reference Doses

The U.S. EPA has employed an ADI approach for deriving levels to protect exposed

populations from noncarcinogenic adverse effects of pesticides in foodstuffs and pollutants in

ambient waters (Federal Register, 1980). U.S. EPA developed an oral reference dose (RfD)

concept in 1987 (Barnes and Dourson, 1988). The RfD is comparable to previous ADI methods

but presents a more developed protocol for study selection, identifying No Observed Adverse

Effect Levels (NOAELs), applying uncertainty factors, and assessing the weight of evidence. As

of May, 1996, U.S. EPA RfDs were available for over 200 substances (U.S. EPA, 1996). The

major limitation of these values is that they are almost entirely based on noninhalation exposure

data rather than inhalation exposure data.

1.8.3 Occupational Threshold Limit Values

Occupational exposure limits have been used to derive chemical exposure guidelines for the

general public (National Air Toxics Information Clearinghouse, 1991; Robinson and Paxman,

1992). As of May, 1996, more than 600 American Conference of Governmental Industrial

Hygienists (ACGIH) TLVs (ACGIH, 1996) and National Institute for Occupational Safety and

Health (NIOSH) RELs (NIOSH, 1990) were available. These values have been attractive

because of the large number of available values and the concept that they are intended to protect

a human population from inhalation exposures. However these values lack a consistent basis, are
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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not designed for or recommended for protection of the general public, and in many cases may not

prevent adverse health effects among most workers (Roach and Rappaport, 1990).

1.8.4 California Ambient Air Quality Standards

California Ambient Air Quality Standards (CAAQS) are available for criteria air pollutants

(CAPCOA, 1993). Where defined according to a basis appropriate to lifetime exposures, the

CAAQS was adopted as the chronic inhalation REL.

2. Hazard Identification

2.1 Selection of Key Studies

An important step in the development of a chronic REL is the identification of research

studies that contribute most significantly to the weight of evidence as to the degree of hazard

presented to humans by a particular substance (U.S. EPA, 1994). These studies may involve a

human population studied in an epidemiological, clinical, case, or experimental exposure setting,

or they may involve experimental studies with animals. The key studies are given greatest

weight in estimating a threshold for adverse effects and in identifying the nature of the critical

adverse effect.

2.1.1 Human Data

Human data are logically most relevant to assessing human health effects associated with

chemical exposures. Much of the available human exposure data is via inhalation. Principles for

evaluating human exposure studies for use in determining health-based exposure levels have

been discussed (NRC, 1985).

Three types of human studies have been used in assessing health effects of chemicals: (1)

epidemiological studies, (2) controlled exposure experiments, and (3) case reports. Each of these

three study types can provide important information needed to protect public health. When using

these studies for risk assessment, several factors are important in evaluating their quality and in

determining the level of certainty associated with their use.

2.1.1.1 Epidemiological Data

Epidemiological studies generally result in data on effects of chemical exposure to a large

number of persons. Areas of concern include exposure measurement, health effects

measurement, and accounting for covariables and confounding variables. The population studied

often consists of employees exposed at the workplace to varying concentrations of airborne

chemicals.

Exposure measures frequently represent the greatest weakness of available epidemiological

studies. Continuous, long-term exposure monitoring of individual subjects is rarely available.

Frequently it is necessary to use limited, short-term exposure monitoring data, which in many

cases are not specific to the individuals under study, in order to derive an estimate of what the
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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individual exposures may have been. Occupational exposures may vary over time as industrial

hygiene practices change and individuals change jobs. The degree to which air concentrations

can be adequately estimated is critical in determining the usefulness of an epidemiological study.

Health effect measures in epidemiological studies also frequently differ from those reported

in experimental animal studies and must be carefully examined. Human health effect

measurement generally consists of recording observable effects and conducting non-invasive

tests. Health effects data are compared with those compiled from a non-exposed group and may

be presented as incidence, standardized mortality ratios, or relative risk ratios. Health effects

with a long latency may be missed if the time period of the study is inappropriate.

Co-variables and confounding variables should be controlled or removed from the study.

Co-exposure to other chemicals is an important concern as a potentially confounding effect.

Occupational studies raise an additional concern in that generally healthy workers may be

less sensitive to the adverse effects of chemical exposures than others in the general population,

including children, the elderly, and persons with preexisting medical conditions. Bias may also

be present where a workplace is disproportionate by gender (NRC, 1985).

Negative epidemiological studies present an additional difficulty in interpretation.

Estimating the power of the study to detect adverse effects can be useful in providing an

indication of the maximum incidence consistent with the failure to show that the exposed group

was statistically different from the control group.

2.1.1.2 Controlled Human Exposure Studies

Controlled exposure studies have the advantages (1) of having quantified exposure

concentrations and (2) of being conducted with human subjects, thus combining two important

features of human epidemiological and animal toxicity studies (Hackney and Linn, 1983). The

limitations of such studies are that they usually (1) involve small sample sizes, (2) are of very

short exposure duration, and (3) assess effects through noninvasive and sometimes subjective

measurements that might miss significant health effects.

2.1.1.3 Case Reports

Individual case reports of adverse effects associated with exposures to a chemical can be

useful, especially as qualitative confirmation that effects observed and quantified in animals also

occur in exposed humans. These reports are generally not appropriate for quantitation because of

the very small sample size and the unquantified exposures (Goldstein, 1983). Exposures are

frequently much higher than threshold doses, with serious injury occurring. Multiple case

histories with the same endpoint are especially relevant.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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2.1.2 Animal Data

Over 4,000 chronic animal exposure studies have been conducted. Many of these studies

were primarily concerned with assessing chemical carcinogenic potential, though evaluations of

noncancer health effects were generally included (Gold et al., 1991).

Identification of the most appropriate animal species requires consideration of all available

data relevant to prediction of human effects from animal observations. Studies of the most

sensitive endpoints have frequently been selected as key studies. The most sensitive endpoint

will be influenced by the relative sensitivity of species tested and by the relative sensitivity of

tests employed. However, the animal species most sensitive to a substance is not necessarily that

most similar to humans in developing adverse effects from a particular exposure. Selection of

the animal model and key study can be influenced by what is known about human health effects,

and relevant areas of similarity and dissimilarity between humans and the animal species may be

established (Calabrese, 1983). Comparison of human and animal pharmacokinetics, metabolism,

and mechanism of action may be useful in selecting the relevant animal model for predicting

human health effects. However, in most instances it is not possible to determine which species is

more like humans in response to a chemical exposure.

An experimental study should have a clear rationale and protocol, use Good Laboratory

Practice Standards, and use appropriate analysis methods. Experimental study designs and

criteria recommended by the NTP have been reviewed (Chhabra et al., 1990). Because more

recent studies have been done by investigators aware of such guidelines, preference for use has

usually been given to more recent studies. Appropriate statistical analysis of the results is

important (Muller et al., 1984). However, the goal of protecting public health must be weighed

with experimental design so that important endpoints are not missed and so that responses of

relevant species are not ignored. Furthermore, it is important that there not be any disincentive to

conducting good studies in order to avoid the establishment of reference exposure levels.

2.2 Weight of Evidence

U.S. EPA has used a categorical ranking of the weight-of-evidence for U.S. EPA RfCs

(U.S. EPA, 1997). OEHHA has not adopted such a formal scheme, but a descriptive analysis of

strengths and uncertainties of each REL has been presented. Issues such as observation of a

dose-response relationship, reproducibility of findings, and mechanism of action were given

weight in the OEHHA evaluation of chronic inhalation RELs.

2.2.1 Strength of Associated Adverse Health Effect

The strength of an association between chemical exposure and adverse effect is assessed.

Strength of association can be measured in terms of high observed effect incidence or relative

risk, statistical significance of differences between control and exposed groups, and a positive

dose-response relationship. For example, if an adverse effect noted in a low exposure group was

not noted in a high exposure group, evidence for a causal association between the chemical

exposure and the effect is greatly reduced.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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2.2.2 Consistency of Associated Adverse Health Effect

Consistency of an association between chemical exposure and adverse effect is also

evaluated. Relevant observations include similarity of effects noted in different studies and

among different populations and/or species, and consistency of effect for different routes of

exposure. For example, if an effect was noted in only one of many studies of a particular strain

of laboratory rodent, evidence for a causal association between the chemical exposure and the

effect is weakened.

2.2.3 Specificity of Associated Adverse Health Effect

If an adverse health effect is specific to exposure to a substance, the case for causality is

strengthened. Such highly specific relationships are unusual, however, as chemical exposures

generally cause multiple effects and chemical-induced health effects are sometimes comparable

to similar health effects of known or unknown etiology observed in the absence of exposure.

2.2.4 Temporal Association

To strengthen the causal relationship, the adverse health effect should occur at a time

following exposure that is consistent with the nature of the effect. For example, respiratory

irritation immediately following exposure to an irritant vapor is temporally consistent, whereas

effects noted years later may not be. On the other hand, tumors, noted immediately following

exposure, might be temporally inconsistent with a causal relationship, but tumors arising after a

latency period of months or years would be temporally consistent. An issue of temporal

association that is sometimes difficult to clarify is the distinction between an effect due to

chronic exposure and an acute effect due to repeated acute exposures. It may be inappropriate to

develop a chronic REL based on an endpoint that is essentially an acute health effect seen

repeatedly with daily workplace exposure.

2.2.5 Coherence of Adverse Health Effect

Coherence or scientific plausibility of the association is also examined. This is assessed in

terms of evidence that the effects are consistent with what is known about the pharmacokinetics

and mechanism of action of the chemical.

3. Dose Response Assessment

3.1 Estimation of Threshold or Low Response Concentrations

Noncancer health effects assessment has been rooted in the concept that a threshold

concentration or dose exists below which no adverse effects would occur. While such thresholds

are observed among individuals, the existence and magnitude of a population threshold below

which no members of the population would experience adverse effects cannot be demonstrated.

The entire population of concern is not examined, rather a sub-population from which inferences
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

17

are drawn is studied. Therefore, it is not possible to distinguish whether a concentration is truly

below a population threshold level for an adverse effect or is rather a level associated with a

relatively low incidence of adverse effects which cannot be distinguished from background rates

in the population.

3.1.1 Use of No-Observed-Adverse-Effect-Levels (NOAEL)

A No-Observed-Adverse-Effect-Level (NOAEL) may be defined as an exposure level with

no biologically or statistically significant increase in the frequency or severity of adverse effects

among an exposed population relative to a control group. The NOAEL must be tempered by

appropriate statistical interpretation. A NOAEL is sometimes incorrectly viewed as an estimate

of a threshold level for adverse effects. However, a NOAEL could be associated with a

substantial (1 – 20%) but undetected incidence of adverse effects among the exposed population,

or alternatively it could be many-fold lower than a true population threshold (Gaylor, 1992;

Leisenring and Ryan, 1992.) This is so because only a subset of individuals from the population

has been observed, and because the experiment may not have been designed to observe all

adverse effects associated with the substance. Therefore one may not safely conclude that the

study concentration or dose is not associated with any adverse effects. Experimental exposure

levels are usually selected after consideration of certain factors, such as the demonstration in a

prior study of toxicity at that concentration with a shorter exposure duration.

In general, OEHHA has considered a NOAEL without an associated LOAEL identified in

the same study (termed a free-standing NOAEL) to be acceptable for use in deriving a chronic

REL, as long as the overall health hazard information for that substance is consistent with the

NOAEL study. For example, in many cases shorter duration studies involving slightly higher

concentrations have reported adverse health effects.

3.1.2 Use of Lowest-Observed-Adverse-Effect-Levels (LOAEL)

A Lowest-Observed-Adverse-Effect-Level (LOAEL) may be defined as the lowest exposure

level with a biologically or statistically significant increase in the frequency or severity of

adverse effects among an exposed population relative to a control group. The highest exposure

concentration which results in biologic effects that are not considered adverse may be termed the

lowest observed effect level (LOEL); this is identical to the NOAEL (U.S. EPA 1994). If a

NOAEL is not identifiable from the literature, it is estimated for the purposes of risk assessment

from the lowest exposure concentration reported to produce the adverse effect or LOAEL. An

uncertainty factor is applied to the LOAEL to estimate the NOAEL:

LOAEL/UF = NOAEL

A one-to-ten-fold uncertainty factor has been proposed to account for the higher health risk

potentially associated with a LOAEL compared with a NOAEL. This factor has been considered

appropriate for both inhalation (U.S. EPA, 1994) and oral routes of exposure.

The effectiveness of a ten-fold LOAEL-to-NOAEL uncertainty factor was examined for

several inhalation (Mitchell et al., 1993, Alexeeff et al., 1997, Kadry et al., 1995) and oral
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

18

(Dourson and Stara, 1983) exposure data sets. Mitchell et al. (1993) evaluated the LOAEL-toNOAEL ratio for 107 subchronic and chronic inhalation studies. They reported that 15 of the

107 studies had LOAEL-to-NOAEL ratios of 10 or greater. Alexeeff et al. evaluated 210 acute

inhalation studies for 66 chemicals and reported that the LOAEL to NOAEL ratio for mild

effects had 90th and 95th percentiles of 5.0 and 6.2, respectively. In contrast, the ratio of the

LOAEL for serious effects to the NOAEL for all effects had 90th and 95th percentiles of 12 and

40, respectively. Kadry and associates (1995) showed that among a small data set (4 chemicals)

LOAEL to NOAEL ratios were less than 5. However, where only a LOAEL has been observed,

the magnitude of the difference between the observed concentration and the maximum

concentration where adverse effects would not be detected is uncertain.

OEHHA followed U.S. EPA guidance and precedent in the use of this uncertainty factor.

U.S. EPA use of an uncertainty factor less than ten appears to be somewhat subjective and

lacking in specific criteria as to when it is appropriate. OEHHA thus developed specific criteria

for use of an intermediate uncertainty factor: (1) the effect was of low severity (U.S. EPA grade 5

or below as described in Table 2) and (2) the effect was observed in ≤ 30% of subjects. The

concurrence of these two characteristics suggests that the exposure is likely to be relatively nearer

to the NOAEL. It is suggested that an evaluation of the LOAEL to NOAEL relationship be

undertaken to better evaluate the use of this adjustment factor. Results of such an analysis could

be used to improve the exposure level setting procedure in the future.

Information about the dose-response slope could also be used in deriving an intermediate

LOAEL UF, on the grounds that a lesser UF would be adequate where the dose-response slope

was steep compared with a case where a shallow dose-response relationship is observed. Where

adequate data are available, it is likely that a benchmark concentration would be used.

There was considerable discussion at the September, 1999 Scientific Review Panel meeting

regarding the use of hyperplasia as a toxicological endpoint for setting chronic RELs. The use of

such an endpoint should consider whether the hyperplasia may progress to dysplasia and

neoplasia. In a chronic study, if hyperplasia is the most sensitive endpoint for that chemical, we

have used it as an endpoint for REL development. Hyperplasia can be seen as a normal response

(e.g., to hormones), and is seen in response to a number of irritants, which are not carcinogens.

Where we used hyperplasia as the toxicological endpoint and as a mild effect, the histological

grade was low (e.g., one on a scale of 1 to 5) and, in accordance with Table 2, there was no

increase in organ weight noted. Increasing histological grade, changes in organ weight and other

morphological changes would be cause to view the hyperplasia as a severe effect.
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Table 2. U.S. EPA effect severity levels (U.S. EPA, 1994).

Severity Level Effect Category Effect

0 NOEL No observed effects.

1 NOAEL Enzyme induction or other biochemical change,

consistent with possible mechanism of action, with

no pathologic changes and no change in organ

weights.

2 NOAEL Enzyme induction and subcellular proliferation or

other changes in organelles, consistent with possible

mechanism of action, but no other apparent effects.

3 NOAEL Hyperplasia, hypertrophy, or atrophy, but without

changes in organ weight.

4 NOAEL/LOAEL Hyperplasia, hypertrophy, or atrophy, with changes

in organ weight.

5 LOAEL Reversible cellular changes including cloudy

swelling, hydropic change, or fatty changes.

6 (LO)AEL Degenerative or necrotic tissue changes with no

apparent decrement in organ function.

7 (LO)AEL/FEL Reversible slight changes in organ function.

8 FEL Pathological changes with definite organ

dysfunction which are unlikely to be fully

reversible.

9 FEL Pronounced pathological change with severe organ

dysfunction and long-term sequelae.

10 FEL Life-shortening or death.

NOEL - no observed effect level; NOAEL - no observed adverse effect level; LOAEL - lowest

observed adverse effect level; AEL - adverse effect level; FEL - frank effect level.

3.1.3 Estimation of a Benchmark Concentration (BMC)

The importance of dose-response relationships in the evaluation of effects of chemical

exposure is well established. The NOAEL approach does not explicitly incorporate this

information. This led to explorations of the concept that a concentration estimated to be

associated with a predefined low risk could provide an alternative to the NOAEL (Mantel and

Bryan, 1961; Mantel et al., 1975; Crump, 1984; Dourson et al., 1985; Dourson, 1986; Hartung,
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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1987; Gaylor, 1988; Lewis et al., 1988; Gaylor, 1989). Crump (1984) proposed the term

“benchmark dose” and extensively evaluated this concept.

Suggested risk levels have ranged from one in one million (Mantel and Bryan, 1961) to 10%

(Dourson et al., 1985). U.S. EPA has recently adopted the lower 95% confidence limit of the

dose producing a 10% incidence of the critical effect (derived using an adequately-fitting

statistical model) as a benchmark in the derivation of chronic RfCs (U.S. EPA, 1997). OEHHA

has suggested the use of a benchmark based on the lower 95% confidence limit on the dose

producing 1% or 5% incidence. A 5% benchmark was used in the derivation of acute inhalation

RELs (OEHHA, 1999). The range approximates the lower limit of adverse effect detection likely

to occur in typical human epidemiological and laboratory animal studies (Gaylor, 1992). In the

case of a steep dose-response relationship, the selection of benchmark incidence is not critical.

For many acute exposure studies, 1 and 5% incidence benchmark concentrations differed only

slightly from the study NOAEL (Fowles and Alexeeff, 1997; Fowles et al., 1999).

Several of the chemicals for which OEHHA RELs have been derived have also been the

subject of USEPA RfC analysis using a benchmark concentration approach . Several differences

exist between the use of BMCs by U.S. EPA in its RfC development and that employed by

OEHHA. In order to be consistent with the earlier approach to acute RELs (in which it was

observed that some BMC10s exceeded the observed LOAEL (Fowles et al., 1999)), we used the

BMC05 as our benchmark for chronic RELs. The use of a BMC05 made use of a LOAEL to

NOAEL Uncertainty Factor (UFL) unnecessary in experiments in which a NOAEL was not

observed. It is suggested that further analysis to evaluate the BMC procedure should be

undertaken, and that new REL values should be developed using the BMC approach whenever

data of sufficient quality to support this methodology are available.

3.2 Overview of Extrapolation from Study Data to Human Population

A NOAEL observed in a study may be a concentration that would cause adverse effects

among the general human population exposed continuously over their lifetime. The chronic REL

must also address uncertainties in the available data. These areas of uncertainty are accounted

for with the use of extrapolation factors or uncertainty factors.

Extrapolation methods are used by OEHHA in deriving chronic RELs to account for (1)

exposure discontinuity and (2) interspecies differences in exposure. Extrapolation factors are

based on identification of measurable attributes that are judged to be relevant to addressing an

area of concern.

Uncertainty factors are used by OEHHA in deriving chronic RELs to account for: (1) the

magnitude of effect observed at a LOAEL compared with a NOAEL (Mitchell et al., 1993;

Dourson and Stara, 1983); (2) the potentially greater effects from a continuous lifetime exposure

compared to a subchronic exposure (Bigwood, 1973; Dourson and Stara, 1983; Lehman and

Fitzhugh, 1954); (3) the potentially greater sensitivity of humans relative to experimental animals

not accounted for by differences in relative inhalation exposure (Dourson and Stara, 1983;

Vettorazzi, 1976); and (4) the potentially increased susceptibility of sensitive individuals
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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(Vettorazzi, 1976). In this document these four uncertainty factors will be termed (1) LOAEL

uncertainty factor – UFL (discussed in Section 3.1.2); (2) subchronic uncertainty factor – UFS

(discussed in Section 3.3); (3) interspecies factor – UFA (discussed in Section 3.4); and (4)

intraspecies factor – UFH (discussed in Section 3.5), respectively.

The use of uncertainty factors for determining “safe” or “acceptable” levels has been

discussed extensively in the toxicological literature (Alexeeff and Lewis, 1989; Bigwood, 1973;

Dourson and Stara, 1983; NAS, 1977; U.S. EPA, 1994; Vettorazzi, 1976; Dourson et al., 1996).

Uncertainty factors are used when insufficient data are available to support the use of chemicalspecific and species-specific extrapolation factors. Historically, uncertainty factors have most

often been order-of-magnitude factors, indicating the broad level of uncertainty in addressing the

area of concern. More recently OEHHA and U.S. EPA have used 3-fold (the rounded geometric

mean of 1 and 10) uncertainty factors in areas estimated to have less residual uncertainty (U.S.

EPA, 1997). While the geometric mean is 3.16, an examination of U.S. EPA RfCs demonstrated

that, in practice, a single intermediate UF is calculated by U.S. EPA as 3.00 rather than 3.16,

while two intermediate UFs usually accumulate to 10. Thus, cumulative uncertainty factors

could equal 1, 3, 10, 30, 100, 300, 1000, or 3000.

3.3 Effects of Exposure Continuity and Duration

3.3.1 Differences between Continuous and Discontinuous Exposures

Studies of adverse health effects associated with long-term exposures of humans or

experimental animals generally involve discontinuous exposures. Commonly encountered

exposure scenarios involve exposures of 6 to 8 hours per day for 5 days per week. OEHHA

RELs, however, are intended to protect the general public who could be exposed continuously. In

practice, discontinuous facility emissions are generally adjusted to a continuous daily or annual

average.

The default approach adopted for the chronic RELs presented in this document to account

for differences in effects associated with discontinuous and continuous inhalation exposures to

substances is an equivalent time-weighted average approach. This is the same approach used in

the derivation of U.S. EPA RfCs (U.S. EPA, 1994).

The default approach to estimating an equivalent time-weighted average concentration

(CAVG) from the observed concentration (COBS) in non-occupational studies may be summarized

as:

CAVG = COBS x (H hours per 24 hours) x (D days per 7 days)

The default approach to estimating an equivalent inhalation-weighted average concentration

(CAVG) from the observed concentration (COBS) for occupationally exposed humans is:

CAVG = COBS x (10 m3/day occupational exposure / 20 m3/day total exposure)

x (D days per 7 days)
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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3.3.2 Differences between Lifetime and Less-than-Lifetime Exposures

Studies of adverse health effects associated with exposures of humans or experimental

animals generally involve less-than-lifetime exposures. Commonly encountered exposure

scenarios involve occupational exposures of 5 to 20 years, or exposures to experimental animals

over approximately 10% of their lifetime. The OEHHA chronic RELs, however, are intended to

protect the general public who could be exposed over their entire lifetime.

The default approach used in this document is to adopt the method of U.S. EPA to use a 1 to

10-fold uncertainty factor for subchronic exposures. Subchronic exposures have frequently been

defined as those less than 10% of average life-span, except in the case of mice and rats where 13

weeks has been considered subchronic by U.S. EPA.

U.S. EPA has incorporated intermediate UFs, though their rationale for selecting a

subchronic uncertainty factor has not been clearly presented, and in practice appears to be based

on subjective judgment. To implement an intermediate subchronic UF in response to U.S. EPA

and RAAC recommendations, but using a consistent method, OEHHA used the following

approach: (1) exposures less than 8% of expected lifetime were given a 10-fold UF, (2)

exposures from 8 to 12% of expected lifetime were given a 3-fold UF, and (3) exposures greater

than 12% of expected lifetime were given a 1-fold UF. Average life-spans assumed for humans

and experimental animals are presented in Table 3.

Table 3. Average Life-spans for Humans and Experimental Animals

Species

Approximate average

Life-span (years)1

Subchronic exposure

duration (weeks)2

Baboon 55 ≤ 286

Cat 15 ≤ 78

Dog 15 ≤ 78

Guinea pig 6 ≤ 31

Hamster 2.5 ≤ 133

Human 70 ≤ 364

Mouse 2 ≤ 133

Rabbit 6 ≤ 31

Rat 2 ≤ 13

Rhesus monkey 35 ≤ 182

1 U.S. EPA (1988).

2

Subchronic exposures are usually defined as those over less than 10% of average lifetime

(U.S. EPA, 1994).

3

Special rule adopted by U.S. EPA that exposures of 13 weeks or less are subchronic

regardless of species involved (U.S. EPA, 1994).
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Unlike the extensive exposure concentration-duration-effect analyses that have been

conducted for acute lethality data in experimental animals, only limited work has been done to

compare the differences between acute, sub-chronic, chronic and lifetime exposure scenarios.

Kadry and associates (1995) showed that among a small data set (6 chlorinated chemicals)

subchronic NOAEL to chronic NOAEL ratios were less than 10. Nessel et al. (1995) reported

that for 9 inhalation studies the mean and median subchronic NOAEL to chronic NOAEL ratios

were 4.5 and 4.0 respectively (range = 1 to 8). However, in a study of published animal

NOAELs for a larger group of pesticides, Nair and associates (1995) found that 19 of 148 (13%)

subchronic to chronic NOAEL ratios differed by more than 10-fold. Recently, the U.S. EPA

reported that, based on an analysis of responses to 100 substances, the subchronic to chronic

ratios formed a distribution with a median value of 2 and an upper 95th percentile of 15

(Swartout, 1997); the value of 10 represents the 90th percentile.

3.4 Differences between Human and Animal Susceptibility to Toxic Effects of Chemicals

A great wealth of scientific information shows that species differ markedly in anatomic,

physiologic, and metabolic characteristics, and can vary greatly in terms of susceptibility to

adverse effects from exposure to chemicals. However, risk assessment of chemicals must often

rely on observations of experimental animals. Of the many thousands of chemicals in existence,

most have not been studied in human populations, and, where human studies exist, frequently

there is very poor knowledge of exposures, and confounding factors render cause and effect

conclusions difficult.

These differences can be addressed by considering two specific issues: (1) the determination

of an equivalent human concentration and (2) accounting for the potential for greater human

susceptibility to an equivalent dose.

3.4.1 Determination of a Human Equivalent Concentration

The human equivalent concentration (HEC) approach used by U.S. EPA for RfCs (U.S.

EPA, 1994) was adopted by OEHHA for derivation of chronic inhalation RELs. U.S. EPA has

proposed a number of different HEC schemes depending on the physicochemical characteristics

of the substance (reactive gases, water soluble gases, water-insoluble gases, and particles) and on

the site of toxic action (respiratory effects and systemic effects). Some of the proposed HEC

approaches are very data-intensive and have not been used in practice.

U.S. EPA has to date implemented only three categories: (1) gases with respiratory effects,

(2) gases with systemic effects, and (3) particles with respiratory effects. Of 41 RfCs based on

animal data presented by U.S. EPA, 18 were classified as gases with respiratory effects, 20 were

classed as gases with systemic effects, and 3 were considered as particulates with respiratory

effects. Thus OEHHA also limited its use of HEC extrapolation to these scenarios. The methods

employed have been presented in detail in U.S. EPA (1994) and will be briefly reviewed here.
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3.4.1.1 Gases with Respiratory Effects

The regional gas dose ratio (RGDR) is calculated as the relative minute volume (MV) to

relative surface area (SA) for the lung region of concern:

RGDR = (MVa/MVh) / (SAa/SAh)

Default lung surface area estimates presented by U.S. EPA (1994) were used (Table 4).

Table 4. Default Lung Surface Area Estimates (U.S. EPA, 1994)

Species Extrathoracic

surface area (cm2)

Tracheobronchial

surface area (cm2)

Pulmonary surface

area (cm2)

Guinea pig 30 200 9,000

Hamster 14 20 3,000

Human 200 3,200 540,000

Mouse 3 3.5 500

Rabbit 30 300 59,000

Rat 15 22.5 3,400

Minute volume (volume inhaled per minute) is the product of inhaled volume and

respiratory rate. Minute volumes (MV) in L/min for five animal species were estimated from

body weights (BW) in kg with allometric relationships presented by U.S. EPA (1994):

loge(MV) = b0 +b1 loge(BW)

where b0 and b1 are empirically derived factors from a database of MV and

BW values for various species and strains.

Body weights were estimated from the published experimental study under review or, when

necessary, from strain and gender specific default values presented by U.S. EPA (1994).

Intercept (b0) and slope (b1) values are presented in Table 5.
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Table 5. Intercept and Slope Parameters for Estimating Minute Volume from Body Weight

Species b0 b1

Guinea pig -1.191 0.516

Hamster -1.054 0.902

Mouse 0.326 1.05

Rabbit -0.783 0.831

Rat -0.578 0.821

3.4.1.2 Gases with Systemic Effects

Gases leading to systemic health effects were calculated using the default assumptions used

by U.S. EPA for all systemic RfCs developed to date. The default methodology adjusts the

average exposure concentration by the regional gas dose ratio (RGDR), which for systemicallyacting gases is assumed to be the ratio of the animal blood:air partition coefficient (Hb/g)A to the

human blood:air partition coefficient (Hb/g)H. The following formulae describe the calculation of

the RGDR and HEC:

RGDR = (Hb/g)A / (Hb/g)H

HEC = Average exposure concentration x (Hb/g)A / (Hb/g)H

Where the relevant blood:air coefficients are unknown, U.S. EPA recommends assuming

that (Hb/g)A is equal to (Hb/g)H and thus the RGDR for systemic effects is assumed to equal one.

This assumption was used for all RfCs that have been developed for systemically-acting gases.

Chemical-specific data, where available, were used to estimate the HEC for additional REL

values determined by OEHHA. Where species-specific, but not chemical-specific, data were

available, the default assumption of RGDR = 1 was used. Where both species-specific and

chemical-specific data were lacking, no HEC calculation was used, and a 10-fold interspecies UF

was applied.

3.4.1.3 Particulates with Respiratory Effects

The methodology used by U.S. EPA to derive a regional deposited dose ratio (RDDR) and

corresponding human equivalent concentration for particulates with respiratory effects is more

data-intensive than that applied to gases (U.S. EPA, 1994). U.S. EPA has developed a computer

program, the U.S. EPA RDDR Program (U.S. EPA, 1994). To ensure consistency with U.S.

EPA RfCs, this program was used to calculate RDDR and HEC for OEHHA RELs for

particulates with respiratory effects. Experimentally-determined values for the particle

distribution, characterized by the mass median aerodynamic diameter (MMAD) and geometric
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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standard deviation (sigma g), were input into the program, along with the identity of the

experimental species and experimentally-determined or estimated body weights. Minute

volumes were estimated from body weights and default estimates of lung surface areas were

used. The program outputs deposition and RDDR estimates for different lung regions.

A detailed presentation of the RDDR methodology has been presented previously

(U.S. EPA, 1994). Briefly, the method estimates fractional deposition in different lung regions

for both animal species and humans, and calculates the RDDR as the ratio of animal fractional

deposition to human fractional deposition. Fractional deposition is assumed to be dependent on

minute volume, MMAD, sigma g, and prior deposition in regions through which the particles

have already passed. Deposition efficiency (DE), which is unaffected by prior deposition, is

calculated from minute volume, MMAD, and sigma g using a fitted logistic function. The

function uses impaction diameter (x) estimated from MMAD and minute volume and is fitted for

a given species with two parameters (α and β, Table 6):

Flow rate (Q) ≈ MV / 30

x = MMAD2 x Q

DE = 1 / (1 + e α + βlog10

x

)

Then, fractional deposition is determined by sequentially determining deposition in extrathoracic

(ET), tracheobronchial (TB), and pulmonary (PU) regions.

 Table 6. Parameters for Deposition Efficiency Equation

Species α (ET) β (ET) α (TB) β (TB) α (PU) β (PU)

Human 7.13 -1.96 3.30 -4.59 0.52 -1.39

Rat 6.60 -5.52 1.87 -2.09 2.24 -9.46

Mouse 0.66 -2.17 1.63 -2.93 1.12 -3.20

Hamster 1.97 -3.50 1.87 -2.86 1.15 -7.22

Guinea pig 2.25 -1.28 2.52 -0.87 0.75 -0.56

Rabbit 4.31 -1.63 2.82 -2.28 2.58 -1.99

3.4.2 Accounting for Potentially Greater Human Susceptibility

The default approach adopted is to apply a 10-fold uncertainty factor based on an assumption

that an average human is likely to be at most 10-fold more susceptible to the effects of the

substance than experimental animals. A factor of 10 is generally incorporated for extrapolation

from animals to humans. This is truly an “uncertainty” factor since we are unsure how humans

would respond in contrast to the animals tested. However, the uncertainty factor is based on the

potential for greater sensitivity of humans and the larger surface area of humans (Krasovoskii,

1976; Lewis and Alexeeff, 1989; Rall, 1969; Weil, 1972). This uncertainty factor methodology
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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is in contrast to practice used in cancer risk assessment where an allometric surface area

correction and a 95% confidence interval of the slope of the dose response are used. This

approach is identical to that used by U.S. EPA (1994) and recommended by NAS for drinking

water standards. Limited support for the concept of a ten-fold uncertainty factor was provided by

Dourson and Stara (1983). Khodair and associates (1995) showed that among a small data set (6

chemicals) animal NOAEL to human NOAEL ratios were less than 4. Clearly, additional work

in this area is warranted. Further evaluation of the interspecies uncertainty factor could be done

by following the work of Hertzberg (1989) using the categorical regression analysis. Recently,

Schmidt et al. (1997) evaluated interspecies variation between human and five other animal

species. Sixty compounds had human data that could be matched to one or more animal species.

The animal to human ratio of 10 represented approximately the 85th percentile.

U.S. EPA (1994) has used human equivalent concentration (HEC) extrapolation and a 3-fold

intermediate interspecies uncertainty factor. Thus, U.S. EPA has generally used a 3-fold

uncertainty factor for RfC derivation, because its HEC derivation may account for part of the

species differences in susceptibility. The differences accounted for would be the dosimetric

difference between the species. The remaining 3-fold uncertainty factor is to account for

pharmacodynamic or response differences between the species. This modified approach was also

used by OEHHA in this document where there were sufficient data to justify this approach.

Chemical-specific data were used where available. When chemical-specific data were lacking

but species-specific data were available, health protective default assumptions were used. Where

both chemical- and species-specific data were unavailable, a 10-fold interspecies uncertainty

factor was used.

The 10-fold default uncertainty factor would only be applied after consideration of other

factors that potentially might affect the validity of the default assumption. Such factors include

differences between humans and the test species, such as in absorption, distribution, and

metabolism, that would serve as a basis for predicting interspecies differences in susceptibility.

It would only be applied in those cases where an HEC could not be estimated. An exception was

made for data from studies of non-human primates, where a default factor of three was used

because of their similarities to humans.

3.5 Increased Susceptibility of Sensitive Individuals

Chronic RELs are intended to protect identifiable sensitive individuals from harm due to

chemical exposure. However, RELs may not necessarily protect hypersensitive individuals who

may develop an idiosyncratic response (including allergic hypersensitivity).

Susceptibility to harm from chemical exposure may vary among individuals due to genetic

variability within the population, resulting in lower levels of protective biological mechanisms.

Predisposition to increased metabolic activation or decreased detoxification are just two

examples of how genetic variability influences response to toxicants (Hattis et al., 1987; U.S.

EPA, 1994; Eichelbaum et al., 1992; Grandjean, 1992).
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Susceptibility to chemical-related health effects may vary over time for the same individual

due to changing factors such as age, health status, and activity level. Thus, sensitive individuals

may include children, pregnant women and their fetuses, elderly persons, persons with existing

diseases such as lung, heart or liver disease, and persons engaging in physical activity (U.S. EPA,

1994). Other factors, such as acute illness, may cause short-term variations in individual

susceptibility. Seasonal changes in absorption and toxicity have also been noted in laboratory

animals (Barton and Huster, 1987).

Healthy workers, the subject of most epidemiological studies of long-term chemical

exposures, are often found to have lower rates of morbidity and mortality than the general

population (Monson, 1986; Wen et al., 1983). In studies of experimental animals, highly

homogeneous, healthy strains are generally used. Such strains may have much less variability in

response than a more heterogeneous human population. Animals in poor health were more likely

to experience adverse effects from chronic oral exposure to chemicals than were healthy animals

(Chizhikov, 1973).

A 10-fold uncertainty factor is used to account for the known variability within the human

population. Variability may result from differences in toxicokinetics and toxicodynamics. This

factor accounts for the potential for greater susceptibility in subpopulations, including infants and

children. A high degree of intraindividual variability (2-to-30-fold) in response to chemical

exposure has been reported (Krasovskii, 1976; Weil, 1972). Intraspecies variability has been

recently modeled suggesting a 10-fold factor will protect the 85th percentile (Gillis et al., 1997).

In accordance with U.S. EPA guidelines (U.S. EPA, 1994), when a chronic exposure level is

estimated from a study that includes the assessment of a sensitive human sub-population, an

intraspecies factor of 1 is used. Since the true degree of variability of response in the human

population is unknown, the effectiveness of this method in providing protection to nearly all

individuals is uncertain. Thus, for chronic RELs derived from NOAELs or LOAELs, OEHHA

has generally applied a 10-fold uncertainty factor to address the greater susceptibility of sensitive

individuals. This is identical to assumptions previously employed by U.S. EPA (1994).

As noted by Dourson and Stara (1983), the steepness of the dose-response relationship

affects the adequacy of the uncertainty factor for sensitive individuals. They summarized the

range of dose response slopes reported by Weil (1972), indicating that, based on studies of acute

lethality, a ten-fold factor was health-protective in most cases. However, it should be noted that

dose-response curves for acute lethality exposures are likely to be steeper than those for nonlethal chronic exposures since many more population-based variables are likely to be involved.

Because the true variability is unknown, there may be a portion of the population for whom

the chronic RELs will not be protective. It is OEHHA’s intent that the levels will protect the

general population including those in the high end of susceptibility. As information defining

susceptible individuals becomes available, it is our intent to adjust the methodology as necessary

to protect such individuals. Research is currently underway to further divide the intraspecies

uncertainty factor into subfactors for toxicokinetics and toxicodynamics (Renwick and Lazarus,

1998).
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

29

3.6 Estimation of Inhalation Effects from Oral Exposure Data

Strong weight is given to inhalation exposure-based health effects data. If adequate

inhalation data are unavailable, oral exposure data are also considered. Route-to-route

extrapolation under certain circumstances has been supported by U.S. EPA (1994) and the NRC

(1986). Under some circumstances, the use of route-to-route extrapolation has been questioned.

For example, where chemicals act at the portal of entry, route-to-route extrapolation may not be

possible.

Available data support the use of an additional uncertainty factor for non-inhalation studies

(Owen, 1990). Inhalation absorption coefficients for 32 of 34 (94%) substances were at most 10-

fold higher than oral absorption coefficients for the same substance. The median inhalation/oral

absorption coefficient ratio was 1.0. Fifteen (44%) substances were predicted to have greater

inhalation than oral absorption, and 7 (21%) were predicted to have at least 2-fold greater

inhalation absorption. Two of 34 (6%) substances with greatly (> 10-fold) increased inhalation

absorption relative to oral absorption were metals with very low oral absorption (<1%).

Inhalation absorption of beryllium and elemental mercury was estimated as 500-fold and 7,500-

fold higher than corresponding oral absorption, respectively.

Additional evidence that differences between toxic effects following oral and inhalation

exposures generally differ within a 10-fold dose range was provided by Pepelko (1987; 1991).

Inhalation and oral doses associated with a 25% additional risk of cancer RRD(25) were

estimated for various chemicals. Carcinogens were more potent via oral exposure compared with

inhalation exposure in 15 of 23 rodent data sets, and 20 oral exposure data sets (87%) predicted

inhalation results within a 10-fold factor. Greater than 10-fold differences in potency were found

in rats exposed to asbestos, vinyl chloride, or hydrazine. Proposed explanations for these results

were: (1) greater potency via inhalation due to longer residence time of asbestos fibers in the

deep lung than in the gut; (2) underestimates of low-dose inhalation potency of vinyl chloride

due to exposures at saturation concentrations; and (3) variability in the study quality and design

for hydrazine.

While route-specific differences in absorption and potency may occur, no additional

uncertainty factor was applied for non-inhalation data. Instead, attempts were made to adjust for

absorption when possible, and if data indicated that the oral and inhalation absorption varied

greatly but could not be accounted for, then the oral study was not used.

3.7 Summary of Extrapolation and Uncertainty Factors Used to Derive Chronic RELs

The REL is derived from application of extrapolation and uncertainty factors to the NOAEL,

LOAEL, or BMC. All values are computed without rounding except for the final REL, which is

rounded to a single significant digit.

OEHHA used a maximum overall factor of 3,000 in this document. This is consistent with

U.S. EPA practice in deriving RfCs and with their most recent guidance on the subject (U.S.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

30

EPA, 1994). The range of factors used by U.S. EPA and OEHHA in deriving RfCs and chronic

RELs is summarized in Table 7.

3.8 Documentation of Chronic Reference Exposure Levels

The documentation of the development of RfCs and chronic reference exposure levels is

presented in Appendix A. These summaries present the information upon which the calculations

are based. This discussion includes the following key elements.

• Chronic REL summary

• Physical and chemical properties: Descriptions include information on volatility, density,

water solubility, color.

• Occurrence and use: The typical uses of the chemical are described as well as where it is

likely to be found.

• Effects of human exposure: A brief discussion of pharmacokinetics and metabolism is

included if available and relevant. Studies are described in some detail providing

information on study design; study population; exposure concentration, duration, and

continuity; duration of study; methods used to test for adverse effects; and adverse

effects noted.

• Effects of animal exposure: Effects of animal exposures are reviewed in a manner

comparable to that presented for human exposure.

• Derivation of the chronic REL: The derivation of the chronic REL is presented tabularly.

Strengths and weakness of the REL are presented, and areas of uncertainty are discussed.

• Units for chronic REL: The chronic REL is expressed as an airborne concentration in

either ppm or mg/m3. The conversion between units uses the relationship that 1 ppm of

a gas equals its molecular weight divided by 24.45 (from the partial molar volume at

25°C) and expressed as mg/m3 (at 25°C).

3.9 Chronic Reference Exposure Level Summary

The 95 chemicals for which chronic noncancer reference exposure levels (see definition

below) appeared in the Air Toxics “Hot Spots” Program Revised 1992 Risk Assessment

Guidelines (California Air Pollution Control Officers Association, 1993) were initially evaluated.

Of these, 22 had U.S. EPA RfCs, which were evaluated as potential chronic inhalation RELs.

Some RfCs were adopted. In many cases OEHHA agreed on the choice of key study used by

U.S. EPA but OEHHA had somewhat different approaches to time extrapolation and use of

uncertainty factors. Data on an additional 56 substances from the 1992 list were extensively

evaluated and chronic inhalation RELs were derived using U.S. EPA RfC methodology as

modified by OEHHA. For 17 of the original 95, no chronic REL was developed, either because

(1) no emissions were reported in California by the ARB, (2) existing health effects data were

considered inadequate, (3) evaluation of the substance was pending review in the Toxic Air

Contaminant process, (4) chronic inhalation RELs had already been approved by the Scientific

Review Panel and adopted by the ARB, (5) California Ambient Air Quality Standards already

existed, or (6) no non-pesticidal uses were found for the substance.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

31

In addition, OEHHA developed chronic inhalation RELs for 42 other chemicals on the list of

substances for which emissions need to be quantified. These substances were selected primarily

based on (1) the magnitude of current known emissions in California and (2) the availability of a

strong scientific database on which to estimate a chronic REL. Chronic RELs for an additional

three substances, acetaldehyde, diesel exhaust particulates, and perchloroethylene, have already

been adopted by the Air Resources Board. Thus OEHHA plans to propose chronic REL values

for 121 substances. Peer review of the chronic RELs is occurring in batches. The first group of

22 chronic RELs is listed in Table 8.

A comparison of original U.S. EPA RfCs and additional RELs estimated by OEHHA as

presented in this document suggests that the OEHHA RELs are similar to values that might have

been developed by U.S. EPA (Table 9). Cumulative uncertainty factors for OEHHA RELs were

smaller than those used for U.S. EPA RfCs (Figure 1). The primary difference appears to be the

frequent use by USEPA of a 3 to 10-fold database deficiency (modifying) factor, which has not

been used by OEHHA in deriving RELs since the criteria for use of the factor are not clearly

specified. Individual uncertainty factors tended to be slightly greater for OEHHA RELs, which

may be due in part to U.S. EPA limiting RfC development to chemicals with generally good

health hazard databases.

The OEHHA REL development process emphasized the use of human exposure data

whenever possible. Human data were used for the key study for a higher percentage of chemicals

than was the case for U.S. EPA RfCs (Table 10). This result was achieved even though the

additional chemicals evaluated by OEHHA might be anticipated to have less comprehensive

health data than those previously selected by U.S. EPA for RfC development.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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Table 7. Extrapolation Methods and Uncertainty Factors Used for Proposed OEHHA Chronic

RELs

Method or Factor Values Used

Discontinuous exposure extrapolation Calculated according to U.S. EPA time-weighted

average approach (animal exposure data)

Calculated according to U.S. EPA occupational

inhalation-weighted average approach

(human occupational exposure data)

Human equivalent concentration (HEC)

extrapolation

Calculated according to U.S. EPA RfC approach

(inhalation data)

Calculated according to U.S. EPA RfD approach

(non-inhalation data)

Subchronic uncertainty factor 1 (>12% of estimated lifetime)

3 (8-12% of estimated lifetime)

10 (<8% of estimated lifetime)

LOAEL uncertainty factor 1 (no observed effect)

3 (mild and low incidence (≤ 30%) effect)

10 (moderate to severe, high incidence effect)

Interspecies uncertainty factor 1 (human observation)

3 (animal observation) (for nonhuman primates

and for residual susceptibility differences in

rats, mice, hamsters, rabbits, and guinea pigs

not accounted for by U.S. EPA HEC

approach)

10 (animal observations where chemical- and

species-specific data were unavailable, e.g.,

gerbils)

Intraspecies uncertainty factor 1 (sensitive subpopulation)

10 (normal subpopulation)

Route-to-route extrapolation 

(non-inhalation data)

3,500 μg/m3 per mg/kg-day

Modifying factor 1 (OEHHA proposed chronic RELs)

1 to 10 (U.S. EPA RfCs)

Cumulative uncertainty factor 1 to 3,000 (OEHHA proposed chronic RELs)

30 to 3,000 (U.S. EPA RfCs)
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

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Table 8. OEHHA Chronic REL Summary (first 22 RELs)

Substance (CAS #)

Listed in

CAPCOA

(1993)

Chronic

Inhalation

REL (μg/m3)

Hazard Index

Target(s)

Human

Data

Ammonia (7664-41-7)  ̨ 200 Respiratory system  ̨

Benzene (71-43-2)  ̨ 60 Hematopoietic system;

development; nervous system

 ̨

Chlorinated dioxins

 (1746-01-6) &

dibenzofurans (5120-73-19)

 ̨ 0.00004 Alimentary system (liver);

reproductive system; development;

endocrine system; respiratory

system; hematopoietic system

Chlorine (7782-50-5)  ̨ 0.2 Respiratory system

Ethylbenzene (100-41-4) 3,000 Development; alimentary system

(liver); kidney

Ethylene glycol monoethyl

ether (110-80-5)

 ̨ 70 Reproductive system; hematopoietic

system

Ethylene glycol monoethyl

ether acetate (111-15-9)

 ̨ 300 Development

Ethylene glycol mono-methyl

ether (109-86-4)

 ̨ 60 Reproductive system

Ethylene glycol monomethyl

ether acetate (110-49-6)

 ̨ 90 Reproductive system

Formaldehyde (50-00-0)  ̨ 3 Respiratory system; eyes  ̨

Hydrogen chloride

 (7647-01-0)

 ̨ 9 Respiratory system

Isopropanol (67-63-0) 7,000 Kidney; development

Mercury & mercury

compounds (inorganic)

 ̨ 0.09 Nervous system  ̨

Methyl bromide (74-83-9)  ̨ 5 Respiratory system; nervous system;

development

Methyl chloroform (71-55-6)  ̨ 1,000 Nervous system

Methyl t-butyl ether

 (1634-04-4)

 8,000 Kidney; eyes; alimentary system

(liver)

Methylene chloride

 (75-09-2)

 ̨ 400 Cardiovascular system; nervous

system

 ̨

Nickel & compounds

 (except nickel oxide)

 ̨ 0.05 Respiratory system; hematopoietic

system

Nickel oxide (1313-99-1) 0.1 Respiratory system; hematopoietic

system

Phosphoric acid (7664-38-2) 7 Respiratory system

Propylene glycol monomethyl ether (107-98-2)7,000 Alimentary system (liver)

Propylene oxide (75-56-9)  ̨ 30 Respiratory system
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

34

Table 9. Geometric Mean of the Uncertainty Factors Incorporated for Originally Proposed

OEHHA Chronic Inhalation RELs and U.S. EPA RfCsa

Uncertainty Factor OEHHA RELs Derived

from Inhalation Data

U.S. EPA RfCs

LOAEL 2.6 1.9

Subchronic 2.2 2.1

Interspecies 2.4 2.7

Intraspecies 9.3 8.9

Modifying factor 1.0 2.4

Cumulative 134 238

a

 This table will be updated when all 118 chronic RELs have been finalized and adopted.
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

35

Table 10. Comparison of Relative Use of Human and Animal Data in Deriving U.S. EPA

RfCs and Originally Proposed OEHHA Chronic Inhalation RELsa

Reference Level Human data Animal data

U.S. EPA RfCs 9/43 (21%) 33/43 (79%)

Proposed OEHHA chronic inhalation RELs

(derived from inhalation data)

19/63 (30%) 43/63 (70%)

Proposed OEHHA chronic inhalation RELs

(including those derived from non-inhalation

data)

20/75 (27%) 56/75 (73%)

Overall 29/118 (25%) 89/118 (75%)

a

 This table will be updated when all 118 chronic RELs have been finalized and adopted.

Figure 2. Distribution of Cumulative Uncertainty Factors for Inhalation Data_Based OEHHA

Chronic Inhalation RELs as Originally Proposed and U.S. EPA RfCs

1

3

10

30

100

300

1,000

3,000

OEHHA RELs

USEPA RfCs

0%

5%

10%

15%

20%

25%

30%

35%

40%
Determination of Noncancer Chronic Reference Exposure Levels - February 2000

36

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